Ractopamine is a swine feed ingredient that directs nutrients to improve production efficiencies and increase carcass lean gain. Ractopamine has been approved by the United States Food and Drug Administration (FDA) and registered for use in swine and in cattle. Efficacy studies have demonstrated the effectiveness of ractopamine in increasing carcass leanness, increasing rate of weight gain, and improving feed efficiency through testing in swine and cattle in the United States and other countries around the world. These data have established that pork and beef from ractopamine-fed animals is safe for human consumption, and the FDA approved the product after thoroughly reviewing all data to ensure that it met their stringent human food safety standards. Currently, ractopamine is approved for use in the United States and several other countries. Ractopamine is becoming an accepted tool by the swine and beef industry to improve the production of high value lean pork and beef, and at the same time, reduce the environmental impact of each kilogram of pork and beef produced.
Ractopamine is the United States Adopted Name for the compound (1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanol having the following structure of formula I:

It has two asymmetric carbon atoms. The R,R isomer is the most active, but other isomers are also active. Although an individual isomer can be isolated, an individual isomer is not required and preferably the compound is employed as a mixture of the isomers. Various physiologically acceptable salts of ractopamine are possible and the hydrochloride salt is preferred. Ractopamine is a selective beta-one adrenergic receptor agonist.
U.S. Pat. No. 4,690,951 discloses ractopamine, various formulations of ractopamine, uses of ractopamine, and processes for making ractopamine.
The present commercially available formulation is a solid dry premix (Type A medicated article) comprising 9 g per pound (20 g/kg) of ractopamine hydrochloride with ground corncobs. Said dry premix is then thoroughly mixed by the consumer into appropriate solid feed ingredients to obtain ractopamine hydrochloride amounts of 9-18 grams/ton.
As recently approved for cattle, the commercial formulation for cattle is also a solid dry premix comprising 45.4 g per pound of ractopamine hydrochloride with ground corncobs. This dry premix may be thoroughly mixed by the consumer into appropriate solid feed ingredients to afford 8.2 to 24.6 g/ton of ractopamine hydrochloride for administration to cattle. Also included are directions for mixing the solid dry premix into liquid Type B feeds to afford a liquid Type B medicated feed comprising from 0.82 to 1.15 grams/pound or 0.18 to 0.25% by weight of ractopamine hydrochloride. The pH in the liquid Type B feed is required to be maintained at between 4.5 and 7.5. Daily recirculation is required, as well as recirculation immediately prior to use.
Ractopamine, and its hydrochloride salt, have limited solubility in water of about 3-4% by weight. Adjusting pH with acid or base or suitable buffer does not substantially increase solubility of ractopamine. Although the solid premix, as noted above, is becoming an accepted tool by the swine industry to improve production of high value lean pork, there remains a substantial need for a solution type formulation to expand the potential ways by which ractopamine hydrochloride may be administered. Sick livestock, for example, cannot always be induced to eat solid dry feed.
Enhanced solubility of ractopamine hydrochloride can be obtained in certain alcohol and glycol solvents. This enhanced solubility of greater than 3-4%, however, is achieved at the expense of stability problems. As noted above, ractopamine has three hydroxyl groups bonded to the molecule. The molecule is reactive at the hydroxyl group bonded to the divalent ethan-1,2-diyl moiety. When ractopamine is dissolved in an alcohol, glycol or other polar solvents, the molecule reacts at the ethan-1,2-diyl hydroxy group with the hydroxy group of the solvent to form covalently bonded reaction products. The formation and presence of such reaction products is highly undesirable because the pharmacological properties including safety, and toxicologic properties of such reaction products have not been characterized. Further, such reaction products may adversely impact one or more of the requirements under the United States Food and Drug Administration, FDA Center for Veterinary Medicine, Guideline Nos. 92 and 93 Impurities in New Veterinary Drug Substances and Impurities in New Veterinary Medicinal Products, incorporated herein by reference.
Investigations into the solubility of ractopamine hydrochloride in nonpolar solvents evidenced insufficient solubility for purposes of creating a useful Type A liquid formulation. Surprisingly, it has been found that certain cosolvents can be employed to afford solubility of ractopamine hydrochloride and acceptable stability suitable for a liquid formulation.
Accordingly, one object of the present invention is to provide improved solubilization and stabilization of ractopamine or a physiologically acceptable salt thereof. A further object of the present invention is to provide stable liquid solutions and formulations comprising ractopamine or a physiologically acceptable salt thereof in association with certain cosolvents. A further object of the invention is to provide a process for the preparation of a stabilized liquid formulation.
Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.